This project delineates biochemical and pharmacological properties of sigma receptors and ligands. Sigma receptors are found to modulate in an agonist-antagonist fashion learning and memory impairments induced by drugs acting as antagonists at least three different receptor systems: mecamylamine (the nicotinic acetylcholine receptor), MK-801 (the NMDA/PCP receptor), and nimodipine (the L-type calcium channel). Learning capacities are evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, and the step-down passive avoidance and the water-maze test for long-term memory. PRE-084, a selective sigma ligand discovered at this laboratory, attenuate mecamylamine, MK-801, and nimodipine-induced impairment of memory processes in all three tests. These effects of PRE-084 are antagonized by a sigma receptor antagonist BMY-14802. Utilizing a new sigma receptor ligand synthesized in this laboratory, DAPE (N-(2-[3,4-dichlorophenyl]ethyl)-N-(6-aminohexyl)- (2-[1-pyrrolidinyl])ethylamine), sigma receptors solubilized from rat liver membranes are purified to nearly 2,000-fold via an affinity chromatography. Further purification of the sigma receptors is underway.